Biomedical Research Imaging Center and Department of Radiology , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
Department of Radiology, Obstetrics and Gynecology Hospital , Fudan University , No. 419 Fang xie Road , Shanghai 200011 , People's Republic of China.
Mol Pharm. 2018 Aug 6;15(8):3093-3100. doi: 10.1021/acs.molpharmaceut.8b00192. Epub 2018 Jun 26.
Several studies have suggested that neurotensin receptors (NTRs) and neurotensin (NT) greatly affect the growth and survival of pancreatic ductal adenocarcinoma (PDAC). Developing NTR-targeted PET probes could therefore be important for the management of a pancreatic cancer patient by providing key information on the NTR expression profile noninvasively. Despite the initial success on the synthesis of F-labeled NT PET probes, the labeling procedure generally requires lengthy steps including azeotropic drying of F. Using a straightforward chelation method, here we report the simple preparation of aluminum-F-NOTA-NT starting from aqueous F. The cell binding test demonstrated that [F]AlF-NOTA-NT maintained high receptor-binding affinity to NTR1. This probe was then further evaluated in NTR1 positive pancreatic tumor models (AsPC-1 and PANC-1). After the administration of [F]AlF-NOTA-NT, small animal PET studies showed a high contrast between tumor and background in both models at 1 and 4 h time points. A blocking experiment was performed to demonstrate the receptor specificity: the tumor uptake in AsPC1 without and with blocking agent was 1.0 ± 0.2 and 0.1 ± 0.0%ID/g, respectively, at 4 h post injection. In summary, a NTR specific PET agent, [F]AlF-NOTA-NT, was prepared through the simple chelation method. This NTR-targeted PET probe may not only be used to detect NTR1 positive pancreatic tumors (diagnosis), but also it may be fully integrated to NTR target therapy leading to personalized medicine (theranostic).
已有多项研究表明神经降压素受体（NTRs）和神经降压素（NT）对胰腺导管腺癌（PDAC）的生长和存活有很大影响。因此，开发 NTR 靶向的 PET 探针对于胰腺癌患者的治疗可能非常重要，因为它可以提供关于 NTR 表达谱的非侵入性关键信息。尽管最初在 F 标记的 NT PET 探针的合成方面取得了成功，但标记过程通常需要包括共沸干燥 F 的冗长步骤。在这里，我们使用简单的螯合方法，从水性 F 报告了简单制备铝-F-NOTA-NT 的方法。细胞结合试验表明，[F]AlF-NOTA-NT 保持对 NTR1 的高受体结合亲和力。然后，该探针在 NTR1 阳性胰腺肿瘤模型（AsPC-1 和 PANC-1）中进行了进一步评估。在给予[F]AlF-NOTA-NT 后，小动物 PET 研究显示，在 1 和 4 小时时间点，两种模型中的肿瘤与背景之间的对比度都很高。进行了阻断实验以证明受体特异性：在注射后 4 小时，无阻断剂和有阻断剂的情况下，AsPC1 中的肿瘤摄取率分别为 1.0±0.2 和 0.1±0.0%ID/g。总之，通过简单的螯合方法制备了 NTR 特异性 PET 试剂[F]AlF-NOTA-NT。这种 NTR 靶向的 PET 探针不仅可用于检测 NTR1 阳性胰腺肿瘤（诊断），而且还可与 NTR 靶向治疗完全整合，从而实现个体化医学（诊断和治疗）。
